Although a number of promising anti-amyloid (ABeta) agents are currently in large-scale clinical trials, unfortunately, none of the trials at the stages of mild to moderate Alzheimer's disease (AD) dementia has yet demonstrated clear evidence of clinical benefit. Given the mounting evidence that neurodegeneration is well entrenched even by the stage of MCI, there is growing concern in the field that we may need to institute antiamyloid therapies at a much earlier stage of AD to fully impact the course of the disease. Recent imaging, biomarker, and autopsy studies are remarkably consistent in the finding that approximately 1/3 of clinically normal older individuals harbor ABeta pathology, and many of these individuals already demonstrate functional and structural brain imaging abnormalities consistent with preclinical AD. The A4 (Anti-Amyloid treatment in Asymptomatic Alzheimer's disease) study is a secondary prevention trial in clinically normal older subjects with biomarker marker evidence of AD pathology, who at increased risk for progression to AD dementia. The A4 trial will be a 3-year, double-blinded, placebo-controlled trial of a monoclonal anti-ABeta antibody in 1000 older individuals who are ABeta-positive on screening PET amyloid imaging. The primary outcome will be rate of decline on a cognitive composite, heavily weighted towards episodic memory and executive function tests. Secondary biomarker outcomes will include PET amyloid imaging, cerebrospinal fluid levels of tau/phosphotau, and volumetric MRI measures. We will also develop a novel computerized test battery and task-free functional MRI as exploratory outcomes. The A4 study will also include a natural history arm of age and education matched ABeta-negative individuals (n=500) who will undergo longitudinal clinical and cognitive assessments. The A4 study should provide critically needed evidence to support (or refute) ABeta as a promising strategy for disease-modifying therapy in very early AD, and will serve to greatly enhance the efficiency of future prevention studies as additional therapies, including anti-tau agents, become available.